Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease

Abstract

Cisplatin is an effective chemotherapeutic agent, but significant nephrotoxicity limits its clinical use. Despite extensive investigation of the acute cellular and molecular responses to cisplatin, the mechanisms of progression from acute to chronic kidney injury have not been explored. We used functional and morphological metrics to establish a time-point when the transition from acute and reversible kidney injury to chronic and irreparable kidney disease is clearly established. In mice administered 1 or 2 doses of intraperitoneal cisplatin separated by 2 weeks, kidney function returned toward baseline two weeks after the first dose, but failed to return to normal two weeks following a second dose. Multiphoton microscopy revealed increased glomerular epithelial and proximal tubular damage in kidneys exposed to two doses of cisplatin compared with those exposed to a single dose. In contrast, there was no evidence of fibrosis, macrophage invasion, or decrease in endothelial cell mass in chronically diseased kidneys. Pathway analysis of microarray data revealed regulated necrosis as a key determinant in the development of chronic kidney disease after cisplatin administration. Western blot analysis demonstrated activation of proteins involved in necroptosis and increased expression of kidney injury markers, cellular stress response regulators, and upstream activators of regulated necrosis, including Toll-like receptors 2 and 4. These data

Epidemiologic Characteristics of Acute Kidney Injury During Cisplatin Infusions in Children Treated for Cancer

“…After receiving multiple cisplatin doses, patients may experience unresolved tubular injury, increasing susceptibility of further injury. 44,45 Although further research is needed with larger sample sizes to differentiate the contributions of risk factors and their associations, identified risk factors should be confirmed for identifying future individual cisplatin-associated AKI risk with a goal of early management. It remains unclear how cisplatin dose should be adjusted because of AKI.…”

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease

“…The disconnection of the glomerular tubular junction is a common, but often undetected response to kidney injury 31 . ATG are seen in humans and rodent models of CKD [32][33][34][35][36][37][38] . The ATG were smaller than those with an intact glomerular-tubular junction outside of the lesions.…”

Don’t trick me twice!

“…6,7 Another recent study using folic acid-induced nephropathy is very much in line with the suggested 2-wave model of injury in AKI, also confirming a role for necroptosis in the second wave of injury. 8 Together with the data by Landau et al, 1 necroptosis should be considered a therapeutic target for AKI.…”

“…Mechanisms of AKI-to-CKD transition are subject to intensive research in the kidney community. In this issue of Kidney International, Landau et al 1 report a molecular 2-hit model of AKI-to-CKD transition induced by cisplatin.…”

“…In the USA, for example, 5692 kidney transplantations with living donors, and 14,457 with deceased donors, were performed in 2016. 1 The short-term risks to healthy donors are minimal, but longer-term risks for progressive kidney disease are less certain. The long-term rate of end-stage renal disease in living donors postuninephrectomy is about 8-fold greater, compared with that in similar subjects who have not donated a kidney.…”